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Functional Characterization of Endogenously Expressed Human RYR1 Variants
07:59

Functional Characterization of Endogenously Expressed Human RYR1 Variants

Published on: June 9, 2021

Leaky ryanodine receptors in β-sarcoglycan deficient mice: a potential common defect in muscular dystrophy

Daniel C Andersson1, Albano C Meli, Steven Reiken

  • 1Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. arm42@columbia.edu.

Skeletal Muscle
|May 30, 2012
PubMed
Abstract

Insights

Ryanodine receptor type 1 (RyR1) dysfunction and calcium leak contribute to muscle weakness in Limb-Girdle muscular dystrophy. RyR1 stabilization improved muscle function and exercise capacity in mouse models, suggesting a potential therapeutic target for multiple muscular dystrophies.

Area of Science:

  • Muscle physiology and pathophysiology
  • Molecular mechanisms of muscular dystrophy
  • Calcium signaling in muscle

Background:

  • Dystrophin-glycoprotein complex disruption causes muscular dystrophies like Duchenne muscular dystrophy.
  • In mdx mice, RyR1 dysfunction leads to calcium leak and reduced muscle force.
  • It was unknown if RyR1 dysfunction occurs in other muscular dystrophies.

Purpose of the Study:

  • To investigate RyR1 channel function in a murine model of Limb-Girdle muscular dystrophy (Sgcb-/-).
  • To determine if RyR1 stabilization can improve muscle function in Sgcb-/- mice.

Main Methods:

  • Utilized a Sgcb-/- mouse model deficient in β-sarcoglycan.
  • Analyzed skeletal muscle RyR1 oxidation, nitrosylation, and calstabin1 association.
  • Assessed muscle specific force, calcium transients, and exercise capacity.
  • Administered RyR1 stabilizing compound S107 to Sgcb-/- mice.

Main Results:

  • Skeletal muscle RyR1 in Sgcb-/- mice showed oxidation, nitrosylation, and calstabin1 depletion, leading to increased RyR1 channel open probability.
  • Sgcb-/- mice exhibited reduced muscle force, impaired calcium transients, and decreased exercise capacity.
  • Treatment with S107 improved muscle force, calcium transients, and exercise capacity in Sgcb-/- mice, mirroring findings in mdx mice.

Conclusions:

  • Leaky RyR1 channels are implicated in multiple muscular dystrophies linked to the dystrophin-glycoprotein complex.
  • Dysfunctional RyR1 and altered calcium handling represent a common abnormality.
  • Targeting RyR1 pharmacologically offers a potential therapeutic strategy for Limb-Girdle and Duchenne muscular dystrophies.

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